Non-insulin Dependent Mellitus Research Articles

Decreased mitochondrial DNA (mtDNA) copy number determined by real-time PCR in patients with gestational diabetes mellitus (GDM)

Women with gestational diabetes mellitus (GDM) are at risk of subsequent development of overt diabetes, mainly non-insulin-dependent mellitus (NIDDM), later in life. Although susceptibility to GDM has been suggested to have genetic determinant, the precise genetic basis for GDM is yet unclear. There are some reports that mtDNA content is specifically decreased determine by competitive PCR in adult, but not fetal, pancreatic islets of the Goto-Kakizaki (GK) rat, a genetic model of non-insulin-dependent diabetes. In terms of alterations of the mtDNA content, low birth weight babies were born from mothers whose mtDNA content was decreased. The object of this study is to determine mtDNA copy number using real-time PCR in patients with GDM. Prospective observational study with retrospective analysis. Peripheral blood samples were collected from 68 patients with GDM (age range, 28–33) who were under the inclusion criteria for GDM and from 79 controls. After mtDNA-specific probe and 28S rRNA-specific probe were produced, 5’ and 3’ ends were labeled with FAM reporter and TAMRA quencher. PCR was performed independently for mtDNA and 28S rRNA, respectively. This reaction was performed in triplicate using DNA Engine Opticon 2 (MJ Research). This program measures the detection threshold value (CT), which is defined as the PCR cycles at which a statistically significant increase in reporter fluorescence can be detected above the base line. CT is an inverse proportion to log of target DNA copy number. For the quantification of mtDNA content, a comparative analysis was performed by the amplification of endogenous control (nuclear DNA, 28S rRNA). Between the GDM and control groups, the ratio of mtDNA/28S rRNA was compared using CT of mtDNA of real-time PCR and that of 28S rRNA. All data was expressed as mean±SD. Statistical analysis was performed using Student’s t-test. Statistical significance was set at p < 0.01. In our study, the mean average GDM patient age was 31.7±4.3 years and that of the control group was 31.0 years. The ratio of mtDNA/28S rRNA was 1.205304±0.830688 in GDM patients and 1.797466±1.13551 in control group (p = 0.0004), respectively. In this study, we have used real-time PCR to examine mtDNA copy number in GDM patients and control group that showed decreased in GDM patients compared to control group. Considerable interest has been focused on the quantification of mtDNA in some mtDNA diseases since this severity of clinical symptoms is thought to be related to increased content of abnormal mtDNA. There was also report on decreased mtDNA content in adult pancreatic islets of the GK rat. In terms of decreased mtDNA content in the occurrence of diabetes mellitus, we have applied real-time PCR to analyze mtDNA copy number in GDM and control group. Our result presented here indicated that mtDNA copy number of GDM patients was decreased. Using the Student’s t-test to compare between GDM patients and control group, it was found that there are significant differences in two groups. It can be speculated that metabolic dysfunction may induce mtDNA damage leading to decrease in mitochondrial volume. Our study eventually demonstrated that quantification of mtDNA using real-time PCR is clinically feasible in screening patients with GDM and will further contribute to making an active treatment.

Glycaemic control and its determinants in diabetic patients in Ethiopia

A cross-sectional study was undertaken in which concentrations of glycated haemoglobins were measured in 102 diabetics seen at the outpatient clinic in Gondar, Ethiopia, between 26 January and 7 March, 1995. Mean HbA 1 levels (standard deviations) were 5.35% (1.1) in non-diabetic controls, 12.0% (1.5) in 59 insulin-dependent diabetics, and 11.0% (2.0) in 43 non-insulin dependent outpatients. The majority of insulin-dependent mellitus (IDDM) (78%) and non-insulin-dependent mellitus (NIDDM) patients (77%) were poorly controlled (HbA 1 > 10.8% in IDDM, and > 9.7% in NIDDM, respectively). Multiple linear regression analyses revealed that HbA 1 levels were significantly positively associated with lower body mass index, duration of diabetes, a recent history of polydipsia, hypertension, and low income in NIDDM individuals. Whereas in IDDM patients lower age (or alternatively lower age at onset) was the only significant predictor. Whilst 49% of the model variance was explained by the predictors in NIDDM diabetics, only 9% were so in IDDM patients. Current fasting blood glucose level was marginally significant in NIDDM patients ( r = 0.29; P = 0.058), but insignificant in IDDM individuals. This points towards the fluctuations in blood glucose levels experienced by IDDM patients in a setting where insulin supply is unreliable. It also confirms the doubts about the usefulness of fasting blood glucose values as a tool for assessing metabolic control.

Normalization of insulin secretion by a selective alpha 2-adrenoceptor antagonist restores GLUT-4 glucose transporter expression in adipose tissue of type II diabetic rats.

Noninsulin-dependent mellitus is characterized by the coexistence of defective insulin secretion with insulin resistance in peripheral tissues. Therapeutic objectives are, therefore, to normalize glucose-induced insulin secretion and to restore normal glucose transport into insulin-sensitive tissues. In the present study we evaluate the effects of acute and subchronic administration (2 or 10 days) of the alpha 2-adrenoceptor antagonist SL 84.0418 on glucose tolerance in nondiabetic control rats and type I and type II diabetic rats and the level of the insulin-sensitive glucose transporter GLUT-4, which is exclusively expressed in white and brown adipose tissues, heart, and skeletal muscles. Glucose tolerance and insulin secretion were markedly impaired in type II diabetic rats (neonatal injection of streptozotocin) and were totally corrected by an acute i.p. injection of SL 84.0418. As a consequence of the chronic restoration of insulin secretion, GLUT-4 messenger RNA (mRNA) levels, initially decreased by 67% in white adipose tissue of type II diabetic rats, were normalized by subchronic (10 days), but not acute (2 days), treatment with SL 84.0418. The same results were obtained in brown adipose tissues of type II diabetic rats, whereas no modification of GLUT-4 mRNA levels remained very low in brown adipose tissues of type I diabetic rats (adult injection of streptozotocin) after acute or subchronic administration of SL 84.0418, suggesting that this drug acted by the restoration of insulin secretion. This study reports a decrease in GLUT-4 levels in insulin-sensitive tissues in this model of type II diabetes as well as its regulation after subchronic normalization of insulin secretion. We suggest a direct role for the alpha 2-adrenoceptor antagonist SL 84.0418 in pancreatic beta-cells that allows normalization of glucose tolerance.

Effects of dexfenfluramine of glucose turnover in non-insulin-dependent diabetes mellitus

Dexfenfluramine, a serotonin agonist with effects on the central nervous system (CNS), lowers blood glucose in patients with non-insulin-dependent mellitus (NIDDM). Previous studies using the hyperinsulinemic clamp have shown that dexfenfluramine improves insulin action on both stimulation of glucose uptake and inhibition of hepatic glucose production (HGP). Since the central nervous system can influence glucose tolerance in ways that may not be detected using a clamp procedure, we investigated the effects of dexfenfluramine on glucose kinetics during an oral glucose tolerance test (OGTT) in patients with NIDDM. Glucose kinetics were measured basally and during an OGTT using a double isotope technique and the modified one-pool model of the glucose system. After a 4-week run-in period, studies were performed before, after two 15 mg doses, and then after 4 weeks on 15 mg twice daily in 10 subjects with NIDDM. Fasting-plasma glucose was significantly lower after 4 weeks on dexfenfluramine ( P < 0.01) as was plasma glucose at both 1 and 2 h during the OGTT ( P < 0.05). The lower plasma glucose was associated with a reduction in HGP both basally ( P < 0.01) and during the 1st hour of the OGTT ( P < 0.05). There was no change in peripheral glucose uptake. Plasma insulin levels were unaltered, but plasma glucagon was lower after 1 month of treatment. We conclude that dexfenfluramine improves fasting-blood plasma glucose and oral glucose tolerance predominantly by reducing hepatic glucose production.

Molecular studies of the genetics of non-insulin-dependent diabetes mellitus.

Non-insulin-dependent mellitus (NIDDM) is a common, multifactorial disease with a significant genetic component to disease susceptibility. Biometrical analysis of family data has consistently found evidence of the action of a major gene in determining susceptibility to NIDDM in families. However, the identity of the gene or genes that contribute to NIDDM in the general population is still not known. Recent advances in molecular biology have given investigators access to a number of plausible candidate genes for NIDDM and these have been used as test loci in association and linkage studies with inconsistent results. A review of the candidate gene studies in NIDDM suggests that the failure of these studies to identify specific loci involved in conferring susceptibility to NIDDM is, in part, due to failure to incorporate a number of biological features of the disease. The frequency of NIDDM in the population suggests that the alleles involved in NIDDM are common and their individual impact too small to be detected by simple single locus methods of analysis. Studies of other phenotypic forms of diabetes mellitus suggest that susceptibility to NIDDM is probably determined by alleles at more than one locus acting independently or in concert. The evolutionary history of certain populations may have isolated alleles conferring susceptibility to NIDDM in ethnically defined populations at high risk of NIDDM. These populations may provide a unique opportunity to identify specific genes involved in the complex etiology of NIDDM. © 1993 Wiley-Liss, Inc.

Effect of nifedipine on glucose potentiation of the acute insulin response to arginine in non-insulin-dependent diabetics

The effect of 7-days of nifedipine treatment on insulin secretion has been analyzed in hypertensive patients with non-insulin-dependent mellitus (NIDDM). Pancreatic beta-cell function was assessed as insulin release following stimulation with arginine after potentiation by hyperglycaemia. Two groups of 5 patients with NIDDM (fasting blood glucose 139.2 mg.dl-1), on the same controlled diet, were compared; one was treated with nifedipine 30 mg per d and the other was the control. The mean blood pressure in the nifedipine group decreased (110 vs 102 mm Hg). Fasting blood glucose and basal plasma insulin were not affected by nifedipine. The acute insulin response (AIR) to 5 g arginine after potentiation by hyperglycaemia (clamped at 240 and 350 mg/dl for 30 min) was significantly (P less than 0.05) decreased, as well as the potentiation slope (line relating AIR and plasma glucose level) in those patients, and were unchanged in the control group. Thus, nifedipine may impair insulin secretion at high glucose levels in patients with NiDDM.

Insulin-sensitive tyrosine kinase: relationship with in vivo insulin action in humans

To investigate the relationship of insulin receptor kinase with insulin resistance in humans, we studied insulin-sensitive tyrosine kinase activity in muscle biopsies taken from 20 Pima Indians [14 nondiabetics, 6 with non-insulin-dependent mellitus (NIDDM)] during euglycemic clamps, at insulin concentrations of approximately 68 microU/ml (low dose) and approximately 1,170 microU/ml (high dose). In the nondiabetics, the low dose, insulin-induced kinase activation in vivo was 1.5-fold the activity in the fasting state (P less than 0.05), whereas in the diabetics, the kinase activity actually decreased by 40% relative to fasting (P less than 0.05). The difference in delta-kinase in vivo was significant (P less than 0.01) between the two groups. Similarly, the kinase activation in vitro in response to 1 nM insulin was lower in diabetic subjects compared with nondiabetics (P less than 0.01). These data indicate that, in NIDDM, both in vitro and in vivo insulin-stimulated tyrosine kinase activity is impaired. Among nondiabetics, the kinase sensitivity to insulin, calculated as the ratio of the kinase activity at 1 nM insulin in vitro to the kinase activity at 100 nM insulin, was positively correlated with plasma insulin concentrations 2 h after an oral glucose load (r = 0.69, P less than 0.01). Thus, in nondiabetic subjects with insulin resistance, insulin activation of the kinase is not reduced, but the kinase sensitivity to insulin increases with increasing plasma insulin levels. Therefore, the site of insulin resistance in nondiabetic subjects is distal to the insulin receptor kinase. Furthermore, it is possible that circulating insulin, by increasing the kinase sensitivity to insulin, is a determinant of the receptor kinase activity.

Blood glucose and atherosclerosis.

T relationship of to cardiovascular disease has been known for over half a century and has been the subject of a number of reviews. The topic was discussed by the author and two colleagues in 1975, and the present paper concentrates on information published since that time. Although it is well known that diabetic patients commonly die from cardiovascular disease and that cardiovascular disease is particularly common in diabetes, a number of questions remain unanswered. It is now clear that mellitus consists of at least two distinct disorders that differ both genetically and in their metabolic abnormalities. The majority of diabetics have Type II, or noninsulin-dependent, mellitus (NIDDM), characterized by mild to moderate glucose intolerance, a high frequency of obesity, absence of a tendency to ketoacidosis, and response to treatment with diet or oral antidiabetic drugs. A minority (20%) of diabetics have Type I, or insulin-dependent, mellitus (IDDM), characterized by marked hyperglycemia, weight loss, and a requirement for insulin therapy to prevent the development of ketoacidosis. The old terms of juvenile diabetes for IDDM and maturity-onset diabetes for NIDDM are no longer used, as either type of can occur at any age. The possibility that the two major types of have different relationships to atherosclerosis remains to be explored. The criteria for the diagnosis of are clearly arbitrary, although they correlate with clinical and epidemiological data. Assessment of the severity of is even more arbitrary, while the duration of can only be measured as the time since diagnosis.